Basically substituted amino-acridine derivatives



Patented Apr. 5, 1938 BASICALLY SUBSTITUTED AMINO-AGRI- D1NE DERIVATIVESFritz Mietzsch, Wuppertal-Elberfcld, and Hans Mauss, Wuppertal-Barmen,Germany, assignors to Winthrop Chemical Company, Inc., New York, N. Y.,a corporation of New York No Drawing. Application August '1, 1936,Serial No. 94,876. In Germany May 9, 1930 i 9 Claims.

The present invention relates to new basically substituted acridinederivatives and to a process of preparing the same.

U. S. Patents Nos. 1,760,781, 1,766,403 and 1,889,704- describeprocesses for the manufacture of amino-acridines and substitutionproducts thereof containing basic radicals as substituents in thearomatic amino group. These acridine derivatives are distinguished bytheir remarkable efllcacy to blood parasites.

In accordance with the present invention new S-amino-acrldines areproduced which contain basic substituents in the amino group and ahalogen atom or an alkyl group in the 6-positionand which may containahalogen atom, an alkylor an alkoxy group in the 2-position, moreparticularly acridine derivatives of the formula:

wherein R1 stands for an organic basic radical containing nitrogen, R:stands for hydrogen, an alkyl group or an organic basic radicalcontaining nitrogen, R3 stands for a halogen atom or an alkyl group andR4 stands for hydrogen, a halogen atom or an alkylor alkoxy group. Thesenew compounds are markedly distinguished from the already describednuclear substitution prod- 5 nets of the amino acridines containingbasic substituents attached to the aromatic nitrogen, inasmuch as theydisplay a particularly favorable ratio between therapeutic and toxicaction, whereby it is essential that the new acridine compounds do notcontain nltro groups. They exert a specific activity against theschizont form of the malaria parasites.

The process of manufacture of the new 9- amino-acridines which arebasically substituted in the amino group and contain a halogen atom oran alkyl group inthe G-position and which may contain a halogen atom, analkylor an alkoxy group in the 2-position is by causing bases or saltsthereof, containing at least two basic nitrogen atoms, one of which isin a primary or secondary amino group,.to react with such acridinesubstitution products as contain in the 9-position a replaceablesubstituent and in the 6-position a halogen atom or an alkyl group, andwhich may be substituted in the 2-position by a halogen atom, an alkyloran alkoxy group. Such replaceable substituents in the 9-position are,for example, ether and ester-like groups, such as halogen-, aryloxy-,alkoxy-, aryland. alkyl-mercapto groups.

Accordingly the reaction performed in the said process may berepresented by the following general equation:

wherein R1, R2, R3 and R4 stand for one of the above indicatedsubstituents and X stands for a replaceable etheror ester-like boundsubstituent of the group consisting of halogen atoms, aryloxy-, alkoxy-,aryland falkyl mercaptq groups which have provedequivalent asreplaceable substituents in our present process. The acridinesubstitution products used as starting materials in the said process maybe prepared, for example in accordance with the directions of our U. S.Patent 1,855,302. The reaction is preferably performed in phenolicsolution while heating advantageously on the water bath, wherebysometimes the 9-phenylether of the acridine derivative formed asintermediate product separates, which again is dissolved when enteringinto reaction with the amino compound added. 40

Likewise other organic substances containing hydroxyl or sulfhydrylgroups have proved to be suitable solvents in the present process, forexample, ethylalcohol, glycol, amylalcohol, cresol, naphthol, thiophenoland the like. The reaction temperature is advantageously about C. whenusing these substances as solvents, whereby, if necessary, the reactionis performed in. pressure vessels. Presumably, when using the9-halogen-derivatives as starting materials the reaction sometimes takesplace with the formation of acridines-containing the radical of thesolvent used in ether or thioether-like linkage in the 9-position asintermediate products.

about one to several hours. The new base formed may be separated oil byrendering the reaction mixture alkaline and taking-up the baseprecipitated in an organic solvent, such asether,

. atoms, a distinctly basic character. The radicals may further containsubstituents, for example, the hydroxyl group and ether orthioether-like linkages as specifically described in the numerousexamples. Especially those compounds as contain basic radicalsconstituted 01' aliphatic radicals, such as, for example, thediethyl-amino- 'ethylaminoor the -a-diethylamino- !-pentylamine-radical,are distinguished by their valuable properties in the therapeutic use.

It may be mentioned that for the introduction of the basic radical intothe acridine derivative, bases can likewise be 'used in which, forexample, one of the amino groups is occupied by a radical, which caneasily be split oil, for example, an acyl radical, the acid radicalbeing then subsequently split ofi in the known manner. The introductionof the basically substituted amine into the 9-position can also. becarried out by building up the basic radical in several steps, forexample, by causing an amino alcohol or an amino-substituted halogencompound to act on a substitution product of acridine of the kindspecifled and converting the acridine compounds produced in this manner,containing in the 9-amino group a halogenated or hydroxylated radical(ii necessary, after esterification of the hydroxvl group, for example,by means of a hydrogen halide acid) by means of primary or secondaryamines into the corresponding substitution products oi 9-amino-acridinecontaining a basic radical in the amino group.

Instead of starting from acridines, containing- 7 in the 9-position areplaceable substituent and in the 6-position a halogen atom or an alkylgroup and which can be substituted in the 2-position by a halogen atom,an alkyl or alkoxy group, there can also be used asstartingmaterial,suchacridine compoimds as contain in addition to thereplaceable substituents in the 9-position a substituent in theG-pcdtion whichcan be converted into a halogen atom or an alkyl group byknown methods and which may,'at the same time, contain in the 2-positioninstead of halogen, alkyl or alkoxy, a substituent which can beconverted into those groups or into hydrogen. Such substitucuts areprimarily halogen atoms, hydroxyl-,

7 solution.

nitroand amino groups.

The new acridine derivatives are in the form of the tree bases lightyellow, crystalline substances.

melting at about 100 C. and solublein the usual organic solvents, forexample, ether, alcohol, acetone, benzene, methylenechloride and thelike, in-

soluble in water, but soluble in diluted mineral on one mol. oi. thebase. In general they decompose at about 250" C. and fluoresce inaqueous 2,118,857 'The reaction is complete after heating for Theinvention is illustrated by the following examples without beingrestricted thereto:

I Kaitl n 29.2 grams of 2-ethoxy-6.9-dichloro-acridine (obtainable inaccordance with U. 8. Patent 1,855,302) are dissolved in 120 grams oiphenol at the temperature of the water bath. Without payingregard to theseparation of the 9-phenylether thereby produced 11.6 grams of2-diethylamino-l-aminoethane are added gradually. After stirring for onehour at 100 C. the reaction is complete. In order to remove the phenolthe cooled mass is introduced into zN-caustic soda, whereupon theQ-(dIethyI-amino-ethylamino)-2-ethoxy-6-chloro-acridine is precipitatedin a semi-solid form and is advantageously dissolved in ether. It isreadily solublein most organic solvents. Further puriiicationis carriedout by shaking the ethereal solution with dilute acetic acid,reprecipitating with ammonia and redissolving in ether. By means of anethereal solution of hydrochloric acid there is obtained ahydro-chloride, which is readily soluble in water with a reactionneutral to Congo red and can be recrystallized from alcohol.

Example 2 mr-cmcm-cmcmcm-mcmm 27.8 grams oi.2-methoxy-6.9-dichloroacridine are caused to react in 120 grams ofphenol with 15.8 grams of diethyl-amino-l-aminopentane as described inExample 1. The isolation and puriflcation oi the new base is likewisecarried out as in Example 1. This purification has for its object thecomplete removal of the acridone which is always produced in thereaction. The

base is distinguished by its solubility in ether. The yellowhydrochloride thereof, which is soluble in water with a reaction neutralto Congo red, can be obtained in' the form of a fine crystalline powderby dissolving in methanol and precipitating with ether; it decomposes atExample 3 nn-cH-cmcnrcmmcma,

. Tl n 15.8 oi 5-diethylamino-2-aminopentane are dropped in the courseof one hour at 100 C.

In an analogous manner by starting from,

2-methoxy-6-bromo-9-chloroacridine (compare U. 8. Patent N0. 1,855,302)and a-diethyl-amino-tamino'pmtane, the 2-methoxy-8-bromo-9-(vdi-1.3-tetraethy1diamino-2-chloropropane -2,11s,as7

ethylamino-a-pentylamino) -ac'ridin e forming a hydrochloride, readilysoluble in water, which decomposes at 240-245 C., is obtained.

From 2-methoxy-6-icdo-9-chloracridine (com-- Example 4 )ommcmm lCHI-N(CIHI)I 27.8 grams of 2-methoxy-6.9-dichloro-acridine are dissolvedin 120 grams of phenol and into this solution are dropped at C. withvigorous stirring 20.1 grams of 1.3-tetraethyldiamino-2- aminopropane(mobile colorless liquid, boiling under -8 mm. pressure at 100102 C.),obtainable by the action of potassium phthalimide on (boiling under 13mm.'pressureat 112-113 C.) and subsequent saponification of thecondensation product. The reaction is complete in the course of onehour. Working up follows as in Example 1. The new base dissolves readilyin ether and yields with an ethereal solution of hydrochloric acid ayellow hydrochloride, which decomposes at 225-228 C., and is readilysoluble in water.

Example 5 NE.CH!-CHOH.CHQ.N(CSHK)2 14.6 grams of3-diethylamino-2-hydro'xy-1- aminopropane are stirred at 100 C. in thecourse of one hour into 27.8 grams of 2-methoxy-6. 9- dichloro-acridine,dissolved in 120 grams of phenol. The new base is somewhat sparinglysoluble in ether and is advantageously extracted by means of methylenechloride or chloroform. By dissolving in benzene and precipitating withpetroleum ether it can be obtained as a yellow powder, which melts at-106 C. The yellow hydrochloride thereof dissolves in water with areaction neutral to Congo red and can be crystallized from alcohol. Itwas found to decompose at 238-240 C.

In an analogous manner are obtained:

(a) By employing u-dimethylamino-v-aminopropane (boiling point 36 C.under 10 mm. pressure) as base, 2-methoxy-6-chloro-9 (a-dimethylamino'ypropylamino) -acridine dihydrochloride, decomposing at 255 C. r

(b) By employing m-diethylamino-v-aminobutane (boiling point 61 C. under8 mm. pressure) as base, 2-methoxy-6-chloror9-(a-diethylamino 'y-butylamino) -acrid.ine-dihydrochloride, decomposing at 258-260 C.

(0) By employing a-diallylamino-v-aminobutane (boiling point 75 C. under4 mm. pressure) as base, 2-methoxy-0-chloro-9-(a-diallylamino--butylamino) -acridine-dihydrochloride, decomposing at 208-210 C.

(d) By employing u-dialiylamino-p-aminoethane (boiling point 68-70 C.under 8 mm. pressure) as base, 2-methoxy-6-chloro-9-(a-diallylamino pethylamino) acridine-dihydrochloride, decomposing at 210-212" C.

(e) By employing a-methylamino 'y-aminobutane (boiling point 41 C. under10 mm. pressure) as base, 2-methoxy-6-chloro-9-(a-methyl amino-vbutylamino) acridine-dihydrochloride, decomposing at 210-212 C.

Example 6 v I C1H| mo o O DQ 1 27.8 grams of2-methoxy-6.9-dichloroacridine are condensed in grams oi phenol at 100C. with 23.5 grams of 4-amino-1-N-(ethyldiethylaminoethyl)-aminobenzene. After working up in the customary manner the base remainsas a reddish brown powder, melting at 96-99" C. (not sharp). It yields areddish brown hydrochloride, which dissolves readily in water with a redcoloration, decomposes at 255-258" C. and can be crystallized withalcohol, forming lustrous reddish brown scales. f

The 4 amino- 1 -N- (ethyldiethylaminoethyl) aminobenzene can be obtainedas a water white, mobile oxidizable liquid (boiling at -172 C. under 7mm. pressure) by introducing the nitroso group intoN-(etbyl-diethyl-aminoethyl) -aminobenzene and subsequent reduction.

Example 7 l Gocmcmmcmm moo 1 omcn mcimn Example 8 C Hg-C H! me o d v27.8 grams of Z-methoxy-BS-dichIoro-acridme are in the customary mannercaused to react in readily in methylene chloride.

hydrochloride can be crystallized from alcohol petroleum ether.

120 grams of phenol with 12.8grams oi 2-piperidine-l-aminoethan'e(compare Gabriel, Ber. 24,

page 1,121) The new base, which on working up separates in a solid form,.can be readily recrystallized from alcohol and then forms smallyellowmatted needles, melting at 139-140" C., which dissolve somewhatdimcultly in ether, but more The yellow diand dissolves in cold waterwith some dimculty more readily in hot water. It decom'poses at 260-263C. a. I Example 9 NlLOHa-CHrN acridine and 18.7 grams of the triamine ofthe formula H:N.CH!.CH:.N

cmcmnwusm, are melted in 120 grams of'phenol for one hour at C. The newbascLwhich is obtained in the customary manner is yellow in color,dissolves readily inorganic solvents and is con-" verted by an etherealsolution of hydrochloric acid into a yellow hydrochloride, whichdissolves very readily 225-228" C. The hydrochloride can be crystallizedfrom alcohol. a

When using as starting material instead of the2-methoxy-6-chloro-9-phenoxy-acridine equivalent quantities of, forexample, 2-methoxy-6 chloro-9-methoxy acridine (melting point 158 C.) orof 2-methoxy-G-chIoro-Q-B-naphthoxyacridine (melting point 206-207" C.)or of 2- methoxy-G-chloro-Q-para-tolyl mercapto-acridine (melting pointl55-156 C.) the same product is obtained as above described. In thisconnection it may be said that acridine-derivatives substituted in the9-position by the various radicals oi the kind above mentioned havequite generally proved equivalent in the present in water and decomposesat 'e,11s,ss7

V chloric and; It isa water white, extremely strongly basic liquid,which boils at C. under 11 mm. pressure. 4 v trample 10 27.8 grams of2-methoxy-6.9-dichloro-acridine are caused to react in the customarymanner in' 120 grams of phenolwith 12.2 grams (two molecularproportions) of aminoethyl alcohol, whereby2-methoxy-6-chIoro-Q-hydroxyethyIamino acridine is produced in asatisfactory yield. This new compound can be crystallized from alcoholBIC and yields small yellow matted needles, melting at 191-192. It ismoderately soluble in most solvents. On boiling the benzene solutionwith thionyl chloride on the water bath 2-methoxy-6-chloro-9-chloroethylamino-acridine is readily obtained as a deep yellowpowder, whichin its turn reacts with diethylamine to-iorni 2-methoxy-6-chIoro-Q-diethylaminoethylandno-acridine. The base can be crystallizedfrom benzine in the form of yellow leaflets melting at 117-118 C. Theyellow hydrochloridethereoi is readily-soluble in water and decomposesat 251-252 C.

Furthermore, the same product is obtained when a basically substituted2-alkoxy-6-nitro-9- aminoacridine is transformed into thed-chlorocompound by way of the G-amino-compound. For this purposemolecular quantities of 2- methom-G-nitro-Q-chlor-acridine (from benzeneyellow crystals of the melting point of 214-215 0., obtained from4'-methon-3-nitro-diphenylamine-6-carboxylic acid of the melting pointoi 235-236 C.) and of p-diethylamino-a-aminoethane are condensed afterdissolving in phenol to 2methoxy-G-nitro-Q-diethylaminoethylamino-acridine. After purifying byway or the hydrochloric acid salt the' base crystallizes from benzene inred bright crystals of the melting water. The solution of the free basefluoresces in a remarkable manner. On diazotizing the amino compound adeepred solution is obtained which yields on treating with cuprouschloride according to the Sandmeyer reaction the 2- methoxy-6 chloro 9diethylaminoethylaminoacridine of the above indicated properties.

sample 11 24.8 grams of 6.9-dichloro-acrldine are meltedonaboiiingwaterbathwithgramsotphenol and 17 grams ofa-diethylamino-t-aminopentane are dropped into the melt. Aiter heatingfor 2 hours to 90-100 C. the reaction mixture is introduced into 1000cos. of twice normal caustic soda and the base which separates isextracted by means of ether. The base is purified by extractin theethereal solution with 10% acetic acid and treating the solution inacetic acid with potassium carbonate: finally, it is freed by steamdistillation iromthe last traces oi! the excess of aliphatic diamine.From. the well dried ethereal solution the dlhydrochloride ofd-chloro-il-(a-dietlwlamino-a-pentylaminm-acridine is precipitated bymeans-of ethereal hydrochloric acid, which, by crystallization from alittle alcohol, is obtained in yellow crystals, decomposing at 234-236C.

In a similar manner, by employing a-diethylamino-' -aminobutane as base,B-OhIOIO-Q-(a-dlethylamino- -butylamino) -acridine, decomposing at 240C., is obtained.

The hitherto unknown 6.9-dichloroacridine (crystallizing from benzene insmall, pale yellow crystals melting at 167-168 C.) is obtained from3-chloro-diphenylamine-S-carboxylic acid (crystallizing fromv alcoholin. prisms melting at 200-201 C.) by ring closure and chlorination.

In an analogous manner there is obtained;

(a) From 2-methyl 6.9 -dichloroacridine, 2-methyl-6-chloro9-(e-diethylamino-s-pentylamino) -acridi ne, the "yellowdihydrochloride of which, when crystallized from a mixture of alco- 1101and ether, decomposes at 245-246 C.

For the production of 2-methyl-6.9-dichloroacrldine, 2.4-dichlorobenzoicacid is condensed with 4-toluidine to4'-methyl-3-chloro-diphenylamine-G-carboxylic acid (when crystallizedfrom alcohol melting at 232-233 C.), this compound is subjected to ringclosure and chlorinated. The 2-methyl-6.9-dichloro-acridine forms whencrystallized from benzene pale yellow colored needles, melting at146-147 C.

(12) From 2.6.9-trichloracridine, 2.6-dichloro- 9-(a-diethylamino-a-pentylamino) -acridine. 13y crystallization frommethylalcohol and ether a yellow hydrochloride is produced, which isreadily soluble in water with a reaction neutral to Congo red.

For the production oi. 2.6.9-trichloro-acridine, 2.4-dichlorobenzoicacid is condensed with 4- chloroaniline to3.4-di-chloro-diphenylamino-6- carboxylic acid (when crystallized fromalcohol decomposing at 236-237 0.), this compound is subjected to ringclosure and chlorinated. The

' 2.6.9-trichloro-acridlne forms on crystallizing from benzene smallpale yellow colored crystals, melting at 202-203 C.

(c) From 2-methoxy-6-methyl-9-chloroacridine,2-methoxy-6-methyl-9-(a-diethylamino-tpentylamino).-acridine, the yellowdihydrochloride of which when crystallized from a mixture 01' methylalcohol and ether decomposes at 242.

For the production of 2-methoxy-6-methyl-9- chloroacrldine,4-methyl-2-chlorobenzolc acid is condensed with 4-anisidine to4'-methoxy-3- methyl-diphenylamine-6-carboxylic acid (when crystallizedfrom benzene melting at 182 0.), this compound is subjected-to ringclosure and chlorinated. The 2-methoxy-6-methyl-9-chloro-- dimethyl-9-(e-i'liethylamino-a-pentylamino) -ac-I ridine, the yellowdihydrochloride or which when crystallized from a mixture of methylalcohol and ether decomposes at 219-221 C.

For the production of 2.6-dimethyl-9-chloroac- -ridine'4-methyl-2-chlorobenzoic acid is conmethyl-diphenylamine-B-carboxylicacid (when crystallized from benzene melting at 203 0.), this compoundis subjected to ring closure and chlorinated. The6-methyl-2.'9-dichloro-acridine crystallizes from chlorobenzene in smallgreenish yellowcrystals and at a temperature above 200 C. decomposesgradually with the production of a dark coloration.

(a) From 2-ethyl 6.9 dichloroacridine, 2- ethyl 6 chloro 9-(a-diethy1amino-6-pentylamino) -acridine, the yellow dihydrochlorlde ofwhich, when crystallized from a mixture of al-' cohol and ether,decomposes at 140 C.

For the production of 2-ethyl-6.9-dichloroacridine, 2.4-dichlorobenzoicacid is condensed with 4-ethylaniline to4'-ethyl-3-chloro-diphenylamine-G-carboxylic acid (when crystallizedfrom alcohol melting at 181 0.), this compound is subjected to ringclosure and the condensation product chlorinated. The2-ethyl-6.9-dichloroacridine crystallizes from benzene in weak yellowcolored needles of the melting point 01 102 C.

Example 12y chloric acid salt of the 2-methoxy-6-chloro-9-(4'-amino-methyl-phenylamino)-acridine formed is recrystallized from 3liters of boiling water. The reddish yellow monohydrochloride obtainedis difficultly soluble in cold water and decomposes at 258 C. i

The N-(4-aminobenzyl) -acetamide (from acetone-benzene white crystals ofthe melting point or 93-94 C.) is obtained by reduction or thecorresponding 4-nitro compound by means of iron and acetic acid in thecustomary manner.

Example 13 30.6 grams of 2-isopropyloxy-6.9-dichloroacridine are mixedwith 100 grams of phenol while heating on the water-bath. 16 grams ofa-diethylamino-o-aminopentane are added drop by drop. After heating forone hour at 100 C. the reaction mixture is poured into 1000 cos. of 2-normal sodium hydroxide solution while stirring and the baseprecipitated is taken up with ether. The etheral solution is extractedby means of dilute aqueous acetic acid. From. the acetic acid solutionthe 2-isopropyloxy-6-chloro 9-(adiethylamino-t-pentylamino) -acridine isprecipitated by means of potassium carbonate in the form of the freebase. The latter is taken up with ether and the citrate of the baseprecipitated by means of an ethereal solution of citric acid in the formof a yellow salt which is readily soluble in water.

The 2-isopropyloxy-6.9-dichloroacridine used as starting material formsyellow needles melting I at 132-133 C. when recrystallized from ligroin.It is obtained by condensation of 4-isopropyloxyaminobenzene boiling atC. under 9 mm. pressure with 2.4-dichlorobenzoic acid, subjecting the.4'-isopropyloxy-3-chloro-diphenyiaminefi-carboxylic acid formed (whitishneedles melting at 187-188 C. when recrystallized from alcohol) to ringclosure in the manner known per se and chlorination.

The 2-isopropyloxy-6-chloro-9-(para-diethylaminoethyl-ethylaminophenylamino) acridine is obtained when 23.5 grams of 4-amino-1-N-(ethyl-diethylaminoethyl) -aminobenzene, boiling at 170-172 C. under 7mm. pressure, are used instead of a-diethylamino-t-pentylamine in theabove described process. The base dissolves in ether with a brown redcoloration. From its ethereal solution a reddish brown hydrochloride isprecipitated by means of an ethereal solution of hydrogen chloride.

2-isopropyloxy-6-chloro-9- (para-diethylaminoethoxyphenylamino)-acridineis obtained when using in the above described process 20.8 grams of4-amino-1-diethylaminoethoxybenrene, boiling at 163-164 C. under 7 mm.pressure, as the amine compound. The base dissolves in ether with ayellow red coloration. The water-soluble orange brown hydrochloride isobtained from the ethereal solution by means of ethereal hydrogenchloride solution. 2-isopropyloxy-6 chloro'9-(para-diethylaminoethylmercapto-phenylamino) -acridine is obtainedwhen using in the above described process 22.4 grams of4-amino-1-diethylaminoethylmercapto-benzene, boiling at 149-150 C. under-1 mm. pressure, instead of a-diethylamino li-pentylamine. The basedissolves in other with yellow red coloration and forms an orangecolored water-soluble hydrochloride.

. used as starting material in this case forms yellow crystals meltingat 1115-117" C. when recrystallized from ligroin. It is obtained bycondensing 4-isopropyloxy-1-aminobenzene with 2-chloro-4- bromobenzoicacid, subjecting the 4'-isopropyloxy-3-bromo-diphenylamine 6 carboxylicacid formed (whitish crystals melting at 196-19! C. when recrystallizedfrom alcohol) to ring closure and chlorinating.

2-isopropyloxy-'-6-iodo-9= (a diethylamino 3,3- dimethyl-w-propylamino)-acridine is obtained by reacting upon 2-isopropyloxy 6 iodo 9chloracridine with a-diethylamino-pfi-dimethyl-ypropylamine and'isadvantageously precipitated in the form of its yellow citrate by theaddition of an ethereal solution of citric acid to the ethereal solutionof the acridine base.

The 2sisopropyloxy-fi-iodo 9 chloroacridine used as'starting materialforms iine yellow needles elting at 93-94? C. when recrystallised from iin. It is obtained by condensing 4-isopropyloxy-l-aminobenzene with2-chloro-4-iodo-ben zoic acid in the manner known per se, subjecting the4'-isopropylon 3-iodo-diphenylamine-G-carboxylic acid formed (crystalsmelting at 202' C. when recrystallized frombenzene) to ring closure andchlorinating.

2-n-butyloxy-6-chloro 9 (a-diethylamino-spentylamino) -acridine isobtained by reacting upon 2-n-butyloxy-6.9-dichloroacridine withdiethylamino-t-pentylamine in the manner described above. It forms ayellow citrate which is readily soluble in water. By the addition 0!am-' monia, sodium carbonate or sodium hydroxide to the aqueous solutionof the said citrate the free base is precipitated in the form of an oil.It dissolves readily in alcohol, ether, methylene chlo- 143-144 C. whenrecrystallized from a smallv quantity of benzene. It is obtained bycondensing 4-butyloxy-1-aminobenzene with 2.4-dlchloro-benzoic acid,subjecting the 4'-n-butyloxy- 3-chlorodiphenylamine-6-carboxylic acid(whitish crystals melting at 178-179" C. when recrystallized fromalcohol) to ring closure and chlorinating. g

2-n-butyloxy-6-chloro-9- (a diethylamino p hydroxyy-propylamino)-acridine is obtained by reacting upon the aforementioned 2-n -butyloxy-6.9-dichloroacridine with a-diethylamino-p-hydroxy-y-propylamine. Itforms a yellow hydrochloride which dissolves in water with a greenishfluorescence. 4

Z-n-butyloxy-G-methyl 9 (a-dlfithYlGliflliO-ybutylamino) -acridine isobtained by reacting upon 2-n-butyl-oxy-6-methyl 9 chloroacridine witha-diethylamino-y-butylamine in the manner described above. Itshydrochloride forms yellow crystals decomposing at about C.

The z-n-butyloxy-d-methyl 9 chloroacridine used as starting materialforms yellow crystals melting at 104-.105 when recrystallized fromligroin. It is obtained by subjecting4'-n-butyloxy-3methyl-diphenylamine 6 carboxylic acid (whitish crystalsmelting at 153-154! C. when reto ring closure and crystallized fromalcohol) chlorinating.

2-isoamyloxy --6 chloro-9- (a-diethylamino-liv pentylamino) -acridine isobtained by reacting upon 2-isoamyloxy-6.9-dichloroacridine withadiethylamino-a-pentylamine in the manner described above. Itshydrochloride forms a'yellow powder which readily dissolves in water.

The 2-isoamyloxy-6.9-dich1oroacrldine used as starting material formsyellowish crystals melting at 143-144 C. when recrystallized fromligroin. It is obtained by reacting upon 4-isoamyloxy-1- aminobenzene(boiling at Mil- C. under 10 mm. pressure) with 2.4-dichlorobenzoicacid, subjecting 4'-isoamyloxy-3-chlormdiphenylamine-ficarboxylic acidformed (yellowish greenneedles melting at 181-182 C. when recrystallizedfrom.

alcohol) to ring closure and chlorinating.

2-isoamyloiry-6-chloro-9- (a -diethy1amino hyd'roxy-y-propylamino)-acridine is obtained by reacting upon the aforementioned 2-isoamyloxy6.9.-dichloroacrldine with a-diethyiamino-p-hy-' is readily soluble inwater same as, for instance,

the formiate, acetate, tartrate and lactate. Y The2-hexyloxy-6.9-dichioro-acridine used as starting material forms a lightyellow crystalline powder melting at 124-125" C. when recrystallizedfrom ligroin or benzene. It is obtained by'condensing4-hexyloxy-1-aminobenzene (boiling at 158-160 C. under 10 mm. pressure)with 2.4- dichloro benzoic acid. subjecting the 4'-hexyloxy-3-chloro-diphenylamine-G-carboxylic acid formed (whitish crystals meltingat 144-145 C. when recrystallized from alcohol) to ring closure andchlorinating.

2-hexyloxy-6-chloro-9- (p-N piperidylethyiamino) -acridine is obtainedwhen reacting upon the aforementioned '2-hexyloxy-6.9-dichloroacridinewith N-piperidylethylamine (Ber. der deutschen Chem. Ges. 24 (1891),page 1121).

2-hexyloxy-6-chloro-9- (a-diethylamino 3 hydroxy-q-propyl'amino)-acridine is obtained by reacting upon the aforementioned2-hexyloxy-6.9-

.dichloroacridine with a-diethylamino-p-hydroxy- -propylamine in themanner described above. Its yellow hydrochloride, hydrobromide andbydroiodide are relatively diflicultly soluble in water. They decomposeat about 130-135 C.

2-isooctyloxy-6-chloro- 9 (a dlethylamino-apentylamino) -acrl dine isobtained by reacting upon 2-isooctyloxy-6.9-dichloroacridine withadiethylamino-t-pentylamine in the manner described above. It forms ayellow citrate which is readily soluble in water.

The 2-isooctyloxy-6.9-dichloroacridine used as starting material isobtained by condensing 4-isooctyloxy-l-aminobenzene (boiling at 160 C.un-

der 5 mm. pressure) with 2.4-dichlorobenzoic acid,

pressure and solidifying to a white crystal mass on cooling) with2.4-dichloro-benzoic acid, sub-- jecting the4-decyioxy-3-chloro-diphenylamine.. S-carboxylic acid formed (whitishcrystals melting at 115 C. when recrystallized from ligroin) to ringclosure and chlorinating.

starting material forms yellowish crystals melting at 98-100. C. whenrecrystallized from'iigroin.

It is obtained by reacting upon 4-dodecyloxy-laminobenzene (boiling at213 C. under 6 pressure and solidifying to a white crystal "mass oncooling) with 2.4-dichloro-benzoic acid, subjecting the 4' dodecyloxy 3chlorodipheny i-' 'amine-6-carboxylic acid formed (whitish'crystalsmelting at 115-116 C. when recrystallized. from alcohol) to ring closureand chlorinating.

Emma 14 33.4 grams of 4'risoamyloxy-3-chlorodiphenyiamine-S-carboxylicacid (compare paragraph 15 oi! Example 13) and 21 grams of phosphoruspentachloride are heated'in 200 ccs. of ether during 1 hour whereuponsolution takes-place. On concentrating the solution the acid chloridecrystallizes in the form of a yellow precipitate which decomposes at-110 C. j

35 grams of the acid chloride and 12 grams oia-diethylamino-p-aminoethane are heated to boiling in 100 ccs. ofbenzene while stirring. The benzene is then distilled 01! andthe'basically substituted acid amide is set free from the residue by theaddition ofaqueous caustic soda solution.

It is obtained in the form of a viscous oil.

The amide thus obtained is. heated with 3 times its quantity ofphosphorus oxychloride during 4 hours in a boiling water bath. By and bya'yellow brown solution with a strongly green fluorescence is obtained.The solution is poured on to ice, the 2-isoamyloxy-6-chloro-9- (pdiethyiamino ethylamino)-acridine is precipitated by the addition ofammonia and taken up in ether. The ethereal solution is extracted bymeans of dilute acetic acid solution and the base reprecipitated fromwherein R1 stands for an organic radical selected from the groupconsisting of radicals of the allq'iene and phenylalkylene seriesincluding those radicals the carbon chain of which contains as aninterrupting member an atom selected from the group' consisting ofnitrogen, oxygen and sulfur atoms, R: stands for a substituent selectedfrom the group consisting of hydrogen and alkyl, 21 and a: stand for asubstituent selected from the group consisting of hydrogen, alkyl.aminoalkyl, alkylaminoalkyl and alkylene, the latter group stand for .21and z: jointly, the group being attached to R1 at least once, Ra standsfor a-substituent selected from the group consisting 8oialkylgroupsandhalogenatomsandmstandl for a substituent selected fromthe group consisting of hydrogen, halogen atoms, alkyland alkoxy groups,which acridine derivatives are light yellow crystalline substances,soluble in the usual organic solvents, insoluble in water and soluble indilute acids, and are in the form of their'salts, with acid;water-soluble, crystalline yellow products which decompose atatemperature of about 250 C.

2. Acrldine derivatives of the formula:

wherein R. stands for an alkylene radical and z; and 2: stand for asubstituent selected from the group consisting of hydrogen, alkyl,amino-.

alkyl, alkylaminoalkyl and alkylenc, the latter group standing for 21and z: jointly, R: stands for a substituent selected from the groupconsisting of alkyl groups and halogen atoms, Re stands for'asubstituent selected from the group consisting of hydrogen, halogenatoms, albiand alkoxy groups, which acridine derivatives are lightyellow crystalline substances, soluble in the usual organic solvents,insoluble in water and soluble in dilute, acids, and are in the form oftheir salts with acids water-soluble, crystalline yellow products whichdecompose at a temperature of about 250 C.

3, Acridine derivatives of the formula:

HN-R-N (ml):

wherein R stands for an alblene radical con-' taining up to 5 carbonatoms, Rs stands for a substituent selected from the group consisting ofalkyl groups and halogen atoms, and R4 stands .yellow products whichdecompose at a temperature of about 250 C.

4. Acridine derivatives of the formula:

cl l a N wherein R stands for an alhlene radical containing up to 5carbon atoms, R4 stands for asubstituent selected from the groupconsisting of hydrogen, halogen atoms, alhland alkoxy groups, whichacridine derivatives are light yellow crystalline substances, soluble inthe usual organic solvents, insoluble in water and soluble in diluteacids, and are in the form of their salts with acids water-soluble,crystalline yellow prodauassv uetswhlchdeoomposeatatemperauneor about250' C. a -5. Acridlne derivatives of the formula:

1 HN--R-N(llkll)f moo wherein R stands for an alkylene radical cubtalning up to 5 carbon atoms, which acridine derivatives are li htyellow crystalline substances. soluble in the usual organic solvents,insoluble in water and soluble in dilute acids, and-are in the form oftheir salts with acids water-soluble.

crystalline yellow products which a temperature of about 250 C.

6. Acrldine derivatives of the formula:

decompose at moo wherein It stands for an alkylene' radical con-.talning up to 5 carbon atoms, which acridine derivatives are lightyellow crystalline substances,

which is a light yellow crystalline substance,-

soluble in the usual organic solvents, insoluble in water and solubleindilute acids, and is in the form of its dihydrochlorlde ayellow,-crystalline product which decomposes at 248-250 C.

8. The acridlnederivative of the formula:

which is a light yellow crystalline substance. soluble in the usualorganic solvents, insoluble in water and soluble in dilute acids, and isin the form of its dihydrochloride a yellow, crystalline product whichdecomposes at 234-836 C.

9. The acridine derivative of the formula:

nmcnicnacmcmmclnm moo which is a light yellow crystalline substance,

soluble in the usual organic solvents, insoluble in water and soluble indilute acids, and is in the product which decomposes at 258-260 C.

FRIIZ MIE'IZSCH. HANS MAUSS.

